The overarching goal of this K01 proposal is to explore genetic influences on the developmental heterogeneity of alcohol use disorder (AUD). AUD affects a substantial proportion of US adults, is associated with a variety of psychiatric and medical problems, and represents a significant and costly burden to human health. Research indicates that AUD liability is a function of both genetic and environmental factors, which contribute to wide variation in the manifestation of problems. Epidemiological studies strongly suggest that the development of alcohol problems and related behaviors begins in adolescence, and culminates in the various types of AUD described in the alcohol research literature. An improved understanding of the etiology of AUD can contribute to efforts in prevention, intervention, and treatment by advancing the ability to identify problems early in development and address them in a targeted, appropriate, and effective manner. This proposal delineates a series of training and research goals for the candidate in an effort to advance the understanding of the developmental heterogeneity of AUD and clarify how genetic influences contribute to this variation: i) the candidate will establish expertise in the development and manifestation of AUD through clinical experience in both inpatient and community mental health treatment settings; and through structured readings and discussions with the mentor and co-mentor; ii) a variety of longitudinal modeling methods will be employed to explore the development of alcohol use/misuse alongside associated behaviors from adolescence to early adulthood, culminating in a phenotype that captures an individual's likelihood of membership in different developmental pathways to AUD (e.g., one associated with impulsive behavior, another with depressive symptoms, etc.); iii) genome-wide association studies (GWAS) will be conducted on the phenotypes constructed using longitudinal modeling. The candidate will develop skills in a host of sophisticated secondary analyses including gene-based, network-based, and ontology-based analyses, as well as more global assessments of genomic risk such as the construction of polygenic risk scores and exploration of the heritability of different pathways to AUD; and iv) the candidate will capitalize on previously established expertise in Drosophila genomics to establish a translational program of research, wherein promising candidates identified through the secondary analyses of GWAS data will be validated in a Drosophila alcohol sensitivity/tolerance paradigm. Subsequently, the application of bioinformatic and molecular genetic techniques in Drosophila will be used to generate additional candidates for further exploration in human genomic data. The institutional environment is ideal for the candidate's goal of developing a comprehensive program in alcohol research, and the proposed research represents an important contribution toward advancing the understanding of AUD through a combination of clinical, epidemiological, genomic, and translational methods, consistent with the mission of the NIAAA. PUBLIC HEALTH RELEVANCE: Affecting 20-30% of US adults, and with wide-ranging consequences including psychiatric and medical comorbidities, alcohol use disorders represent a significant public health concern. This project aims to elucidate the influence of genetic factor on alcohol misuse and related behaviors from adolescence through adulthood, and integrates clinical, epidemiological, and translational approaches. Insights gained from this research will inform prevention, intervention, and treatment efforts by clarifying the etiology of developmental paths to alcohol use problems.